Monocytes and macrophages secrete cytokines known as tumor necrosis factor alpha (TNFxcex1) and tumor necrosis factor beta (TNFxcex2) in response to endotoxin or other stimuli. TNFxcex1 is a soluble homotrimer of 17 kD protein subunits (Smith et al., J. Biol. Chem. 262:6951-6954 (1987)). A membrane-bound 26 kD precursor form of TNF also exists (Kriegler et al., Cell 53:45-53 (1988)). For reviews of TNF, see Beutler et al., Nature 320:584 (1986); Old, Science 230:630 (1986); and Le et al., Lab. Invest. 56:234 (1987).
Cells other than monocytes or macrophages also produce TNFxcex1. For example, human non-monocytic tumor cell lines produce TNF (Rubin et al., J. Exp. Med. 164:1350 (1986); Spriggs et al., Proc. Natl. Acad. Sci. USA 84:6563 (1987)). CD4+ and CD8+ peripheral blood T lymphocytes and some cultured T and B cell lines (Cuturi et al., J. Exp. Med. 165:1581 (1987); Sung et al., J. Exp. Med. 168:1539 (1988); Turner et al., Eur. J. Immunol. 17:1807-1814 (1987)) also produce TNFxcex1.
TNF causes pro-inflammatory actions which result in tissue injury, such as inducing procoagulant activity on vascular endothelial cells (Pober et al., J. Immunol. 136:1680 (1986)), increasing the adherence of neutrophils and lymphocytes (Pober et al., J. Immunol. 138:3319 (1987)), and stimulating the release of platelet activating factor from macrophages, neutrophils and vascular endothelial cells (Camussi et al., J. Exp. Med. 166:1390 (1987)).
Recent evidence associates TNF with infections (Cerami et al., Immunol. Today 9:28 (1988)), immune disorders, neoplastic pathologies (Oliff et al., Cell 50:555 (1987)), autoimmune pathologies and graft-versus-host pathologies (Piguet et al., J. Exp. Med. 166:1280 (1987)). The association of TNF with cancer and infectious pathologies is often related to the host""s catabolic state. Cancer patients suffer from weight loss, usually associated with anorexia.
The extensive wasting which is associated with cancer, and other diseases, is known as xe2x80x9ccachexiaxe2x80x9d (Kern et al., J. Parent. Enter. Nutr. 12:286-298 (1988)). Cachexia includes progressive weight loss, anorexia, and persistent erosion of lean body mass in response to a malignant growth. The fundamental physiological derangement can relate to a decline in food intake relative to energy expenditure. The cachectic state causes most cancer morbidity and mortality. TNF can mediate cachexia in cancer, infectious pathology, and other catabolic states.
TNF also plays a central role in gram-negative sepsis and endotoxic shock (Michie et al., Br. J. Surg. 76:670-671 (1989); Debets et al., Second Vienna Shock Forum, pp.463-466 (1989); Simpson et al., Crit. Care Clin. 5:27-47 (1989)), including fever, malaise, anorexia, and cachexia. Endotoxin strongly activates monocyte/macrophage production and secretion of TNF and other cytokines (Kornbluth et al., J. Immunol. 137:2585-2591 (1986)). TNF and other monocyte-derived cytokines mediate the metabolic and neurohormonal responses to endotoxin (Michie et al., N. Engl. J. Med. 318:1481-1486 (1988)). Endotoxin administration to human volunteers produces acute illness with flu-like symptoms including fever, tachycardia, increased metabolic rate and stress hormone release (Revhaug et al., Arch. Surg. 123:162-170 (1988)). Circulating TNF increases in patients suffering from Gram-negative sepsis (Waage et al., Lancet 1:355-357 (1987); Hammerle et al., Second Vienna Shock Forum pp. 715-718 (1989); Debets et al., Crit. Care Med. 17:489-497 (1989); Calandra et al., J. Infect. Dis. 161:982-987 (1990)).
Thus, TNFxcex1 has been implicated in inflammatory diseases, autoimmune diseases, viral, bacterial and parasitic infections, malignancies, and/or neurogenerative diseases and is a useful target for specific biological therapy in diseases, such as rheumatoid arthritis and Crohn""s disease. Beneficial effects in an open-label trial with a chimeric antibody to TNFxcex1 (cA2) have been reported with suppression of inflammation (Elliott et al., Arthritis Rheum. 36:1681-1690 (1993)).
The present invention pertains to the discovery that co-administration of a CD4+ T cell inhibiting agent and a tumor necrosis factor (TNF) antagonist to an individual suffering from a TNF-mediated disease produces a significantly improved response compared to that obtained with administration of the inhibiting agent alone or that obtained with administration of the antagonist alone. As a result of Applicants"" invention, a method is provided herein for treating and/or preventing a TNF-mediated disease in an individual comprising co-administering a CD4+ T cell inhibiting agent and a TNF antagonist to the individual in therapeutically effective amounts. The present invention further relates to a method for treating and/or preventing recurrence of a TNF-mediated disease in an individual comprising co-administering a CD4+ T cell inhibiting agent and a TNF antagonist to the individual in therapeutically effective amounts. TNF-mediated diseases include rheumatoid arthritis, Crohn""s disease, and acute and chronic immune diseases associated with an allogenic transplantation (e.g., renal, cardiac, bone marrow, liver, pancreatic, small intestine, skin or lung transplantation).
Therefore, in one embodiment, the invention relates to a method of treating and/or preventing rheumatoid arthritis in an individual comprising co-administering a CD4+ T cell inhibiting agent and a TNF antagonist to the individual in therapeutically effective amounts. In a second embodiment, the invention relates to a method of treating and/or preventing Crohn""s disease in an individual comprising co-administering a CD4+ T cell inhibiting agent and a TNF antagonist to the individual in therapeutically effective amounts. In a third embodiment, the invention relates to a method of treating and/or preventing acute or chronic immune disease associated with a transplantation in an individual comprising co-administering a CD4+ T cell inhibiting agent and a TNF antagonist to the individual in therapeutically effective amounts.
A further embodiment of the invention relates to compositions comprising a CD4+ T cell inhibiting agent and a TNF antagonist.
CD4+ T cell inhibiting agents useful in the methods and compositions of the present invention include antibodies to T cells or to their receptors, antibodies to antigen presenting cells (APC) or to their receptors, peptides and small molecules blocking the T cell/APC interaction, including those which block the HLA class II groove, or block signal transduction in T-cell activation, such as cyclosporin and cyclosporin analogs, and antibodies to B cells.
TNF antagonists useful in the methods and compositions of the present invention include anti-TNF antibodies and receptor molecules which bind specifically to TNF; compounds which prevent and/or inhibit TNF synthesis, TNF release or its action on target cells, such as thalidomide, tenidap, phosphodiesterase inhibitors (e.g, pentoxifylline and rolipram), A2b adenosine receptor agonists and A2b adenosine receptor enhancers; and compounds which prevent and/or inhibit TNF receptor signalling.
In a particular embodiment of the invention, an inflammatory mediator other than a TNF antagonist can be used instead of or in addition to the TNF antagonist.